According to a Summary of National Health and Nutrition Examination Survey Results 2007 published by the Ministry of Health, Labour and Welfare, it is estimated that there are approximately 8,900,000 people who are “strongly suspected of having diabetes” and approximately 13,200,000 people who are “likely to have diabetes” in Japan. That is to say, it is predicted that a total of approximately 22,100,000 Japanese people are affected with diabetes or belong to a diabetes high-risk group. Diabetes has characteristics such as an increase in the fasting plasma glucose level, insulin resistance, acceleration of gluconeogenesis in the liver, and a reduction in glucose-responsive insulin secretion. In addition, there is a fear that diabetes may increase the risk of developing diabetic nephropathy, retinopathy, nervous disorder, and macroangiopathy, and that it may further lead to a significant reduction in quality of life (QOL), such as the necessity of dialysis, blindness, quadruple amputation, arteriosclerotic disease, and stroke.
For the treatment of diabetes, kinesitherapy, dietetic therapy, and drug therapy are carried out. As agents used in drug therapy, metformin having the action of suppressing gluconeogenesis in the liver and promoting the use of sugar in the skeletal muscle is used as a first-line drug. Then, a sulfonylurea (SU) agent promoting insulin secretion, a dipeptidyl peptidase (DPP)-4 inhibitor (see non-patent document 1), a glucagon-like peptide (GLP)-1 analog (see non-patent document 2), thiazolidinedione that improves insulin resistance, and the like are used as agents of second alternatives. Among these agents, the SU agent stimulates pancreatic β-cells and promotes endogenous insulin secretion (see non-patent document 3). However, there is a case in which the SU agent may cause hypoglycemia as a side effect. Thus, attention should be paid when this agent is used, in particular, for elder people, people with deterioration of renal function, and the case of an irregular dietary habit. In addition, with regard to the SU drug, side effects such as an increase in body weight have also been reported. Moreover, the SU drug has been known to cause primary failure in which no effects are found from an initial administration, or secondary failure in which clinical effects disappear during the administration period.
Glucokinase (hereinafter also abbreviated as “GK”) belongs to a hexokinase family and has an alias “hexokinase IV.” Hexokinase is an enzyme that catalyzes conversion of glucose to glucose-6-phosphate at an initial stage of the glycolysis system in a cell. In the case of three hexokinases other than GK, enzymatic activity becomes saturated at a glucose level of 1 mmol/L or less. On the other hand, GK has low affinity for glucose and shows a Km value close to a physiological blood glucose level (8 to 15 mmol/L). GK is mainly expressed in liver and pancreatic β-cells. In recent years, it has been elucidated that GK is also present in brain. The sequences of N-terminal 15 amino acids are different between GK in the liver and GK in pancreatic β-cells, depending on a difference in splicing. However, they have identical enzymatic properties, and intracellular glucose metabolism via GK is accelerated in response to a change in blood glucose levels from a normal blood glucose level (around 5 mM) to hyperglycemic level after eating (10 to 15 mmol/L).
Through the ages, a hypothesis had been proposed that GK functions as a glucose sensor in the liver and pancreatic β-cells. Recent study results have demonstrated that GK actually plays an important role for the maintenance of systemic glucose homeostasis, so that the hypothesis could be proved. For example, a mouse with a destroyed glucokinase gene had significant hyperglycemic symptoms and died shortly after birth. In addition, in heterozygous GK knockout mice, glucose tolerance was deteriorated and insulin secretion by sugar stimulation was impaired. On the other hand, in normal mice in which GK was excessively expressed, the lowering of a blood glucose level, an increase in the content of glycogen in liver tissues, and the like were observed, and such phenomena were observed also in mice in which diabetes was artificially developed. Furthermore, recent studies have revealed that GK functions as a glucose sensor and plays an important role for the maintenance of glucose homeostasis even in humans. An abnormality in the GK gene was found in a family line of maturity-onset diabetes of the young referred to as “MODY2,” and the correlation between the symptoms of this disease and GK activity was clarified (non-patent document 4). Meanwhile, a family line having mutagenesis for increasing GK activity was also found. In such a family line, fasting hypoglycemic symptoms attended with an increase in the plasma insulin level were also observed (non-patent document 5). From these reports, it is considered that GK functions as a glucose sensor in mammals including humans and plays an important role for regulation of blood glucose. Accordingly, it is considered that a substance having a GK-activating action is useful as an agent for sugar metabolism-related diseases including type II diabetes as a typical example.
According to several reports regarding GK-activating drugs, it has been revealed that there is a considerable risk that drug administration will cause hypoglycemia (non-patent documents 6 and 7). Excessive induction of insulin secretion in the pancreas in a state in which the blood glucose level is low has been suggested as a major cause of the occurrence of this hypoglycemia. A GK-activating drug having a systemic action (pancreas and liver) is considered to have the hypoglycemia risk. Moreover, a GK-activating action in the pancreas is considered to increase stress in pancreatic β-cells, and thus, as in the case of the sulfonylurea agent, the GK-activating drug has the risk of causing dysfunction of the β-cells and deterioration of diabetes, when it is administered for a long period of time. Furthermore, this drug also has the risk of leading to an increase in the amount of body fat and an increase in body weight due to insulin secretion.
As means for avoiding these problems regarding side effects, several GK-activating drugs with high liver selectivity have been reported. For example, patent document 1 describes a thought that blood glucose level can be normalized, while reducing the hypoglycemia risk, by using a liver-selective GK-activating factor. This document describes that the urea compound described in WO2004/002481 was used for evaluation, but does not disclose the chemical structure of a specific compound. In addition, non-patent document 8 reports that a compound represented by the following formula (A):
is a liver-selective GK-activating drug for lowering blood glucose level without increasing insulin secretion. However, this document reports that the aforementioned compound is distributed, rather in a larger amount, in the pancreas, and thus, the action mechanism of liver selectivity has not been clarified. Moreover, non-patent document 9 reports that a compound represented by the following formula (B):
acts as a liver-selective GK-activating drug by being incorporated into the liver by organic anion transporters (OATP1B1 and OATP1B3), by utilizing carboxylic acid substitution on pyridine. However, this document also reports that if the substitution site of carboxylic acid is moved, the pharmacological activity itself disappears.
In the liver, GK is regulated by a glucokinase regulatory protein (GKRP). GKRP competing with glucose binds to GK and then inhibits it. At a physiological glucose level, a majority of GK in the liver binds to GKRP, and it is localized in the nucleus of a hepatocyte. In contrast, at a high glucose level, GK does not bind to GKRP, and thus, phosphorylation of glucose becomes possible. As such, by the action of GKRP, GK activity is regulated in a glucose-dependent manner in the liver (non-patent document 10). In fact, when a liver-selective GK-activating drug was repeatedly administered to Goto-Kakizaki diabetes model rats, the drug exhibited a hypoglycemic action at the same level as that of a systemic GK-activating drug. On the other hand, when such a liver-selective GK-activating drug was repeatedly administered to normal rats, the drug did not lower the blood glucose level, while a systemic GK-activating drug lowered the blood glucose level of the normal rats. As a result, it was demonstrated that the liver-selective GK-activating drug has the hypoglycemia risk that is lower than that of the systemic GK-activating drug (non-patent document 9). From these results, the liver-selective glucokinase-activating drug is anticipated to be a new type of glucokinase-activating antidiabetic drug, which reduces side effects caused by systemic GK-activating drugs by controlling blood glucose level in a glucose-dependent manner. However, as described above, there have been only a few reports regarding liver-selective GK-activating drugs, and thus, it is still difficult to design a liver-selective compound intentionally.
As an antidiabetic drug having the phenylacetamide skeleton of the present invention, which is based on a GK-activating action, a compound represented by the following formula (C) has been reported (patent document 2).
(wherein Q represents aryl, 5- or 6-membered ring heteroaryl, or 4- to 8-membered heterocycle; T represents a heterocycle, which is linked to form a heteroaryl ring together with —N═C—, or in which only the N═C bond is an unsaturated portion; R1 and R2 each independently represent hydrogen, hydroxy, halogen, cyano, nitro, vinyl, ethynyl, methoxy, OCFnH3-n, —N (C0-4 alkyl)(C0-4 alkyl), CHO, or C1-2 alkyl (which is optionally substituted with one to five independent substituents selected from halogen, hydroxy, cyano, methoxy, —N (C0-2 alkyl) (C0-2 alkyl), SOCH3, and SO2CH3); or R1 and R2 together form a carbon ring or a heterocycle; or R1 and R2 may together represent an oxygen atom linked to a ring via a double bond; R3 and R4 each independently represent hydrogen, halogen, OCFnH3-n, methoxy, CO2R77, cyano, nitro, CHO, CONR99R100, CON(OCH3)CH3, or C1-2 alkyl, heteroaryl or C3-7 cycloalkyl, which is optionally substituted with one to five independent substituents selected from halogen, hydroxy, cyano, methoxy, —NHCO2CH3, and N(C0-2 alkyl) (C0-2 alkyl); or R3 and R4 together form a 5- to 8-membered aromatic ring, a heteroaromatic ring, a carbon ring, or a heterocycle; R5 and R6 each independently represent hydrogen, hydroxy, halogen, cyano, nitro, CO2R7, CHO, COR8, C(OH)R7R8, C(═NOR7) R8, CONR9R10, SR7, SOR8, SO2R8, SO2NR9R10, CH2NR9R10, NR9R10, N(C0-4 alkyl) SO2R8, NHCOR7, or a C1-4 alkyl group, a C2-4 alkenyl group, a C2-4 alkynyl group, a C1-4 alkoxy group, an aryl group or a heteroaryl group, in which any group is optionally substituted with one to six independent substituents selected from halogen, cyano, nitro, hydroxy, C1-2 alkoxy, —N (C0-2 alkyl) (C0-2 alkyl), C1-2 alkyl, CFnH3-n, aryl, heteroaryl, —COC1-2 alkyl, —CON (C0-2 alkyl)(C0-2 alkyl), SCH3, SOCH3, SO2CH3, and SO2N(C0-2 alkyl)(C0-2 alkyl); or R5 and R6 together form a 5- to 8-membered carbon ring or a heterocycle; R7 and R77 each independently represent hydrogen, or a C1-4 alkyl group, a C2-4 alkenyl group, a C2-4 alkynyl group, a C3-7 cycloalkyl group, an aryl group, a heteroaryl group or 4- to 7-membered heterocyclic group, in which any group is optionally substituted with one to six independent substituents selected from halogen, cyano, nitro, hydroxy, C1-2 alkoxy, —N (C0-2 alkyl)(C0-2 alkyl), C1-2 alkyl, C3-7 cycloalkyl, a 4- to 7-membered heterocycle, CFnH3-n, aryl, heteroaryl, CO2H, —COC1-2 alkyl, —CON (C0-2 alkyl)(C0-2 alkyl), SOCH3, SO2CH3, and SO2N(C0-2 alkyl)(C0-2 alkyl); R8 represents a C1-4 alkyl group, a C2-4 alkenyl group, a C2-4 alkynyl group, a C3-7 cycloalkyl group, an aryl group, a heteroaryl group, or a 4- to 7-membered heterocyclic group, in which any group is optionally substituted with one to six independent substituents selected from halogen, cyano, nitro, hydroxy, C1-2 alkoxy, —N (C0-2 alkyl)(C0-2 alkyl), C1-2 alkyl, C3-7 cycloalkyl, a 4- to 7-membered heterocycle, CFnH3-n, aryl, heteroaryl, CO2H, COC1-2 alkyl, —CON (C0-2 alkyl) (C0-2 alkyl), SOCH3, SO2CH3, and SO2N(C0-2 alkyl) (C0-2 alkyl); R9, R10, R99, and R100 each independently represent hydrogen, or a C1-4 alkyl group, a C3-7 cycloalkyl group, an aryl group, a heteroaryl group or a 4- to 7-membered heterocyclic group, in which any group is optionally substituted with one to six independent substituents selected from halogen, cyano, nitro, hydroxy, C1-2 alkoxy, —N (C0-2 alkyl) (C0-2 alkyl), C1-2 alkyl, C3-7 cycloalkyl, a 4- to 7-membered heterocycle, CFnH3-n, aryl, heteroaryl, COC1-2 alkyl, —CON (C0-2 alkyl)(C0-2 alkyl), SOCH3, SO2CH3, and SO2N(C0-2 alkyl) (C0-2 alkyl); or R9 and R10, or R99 and R100 together form a 6- to 8-membered hetero bicyclic system or a 4- to 8-membered heterocycle, which is optionally substituted with one or two independent substituents selected from C1-2 alkyl, CH2OCH3, COC0-2 alkyl, hydroxy, and SO2CH3; n represents 1, 2, or 3; m represents 0 or 1; and the dotted line optionally forms a double bond together with the solid line, and Δ indicates that the double bond is in (E)-configuration). However, the aforementioned compound is different from the compound of the invention of the present application in terms of the substituents R1 and R2 on the ring Q. Moreover, as for the aforementioned compound there are neither descriptions nor suggestions of possessing a liver-selective action. It has been reported that, in particular, the compound of Example 94 (PSN-GK1), which is a representative compound, has a hypoglycemic action on normal mice, even if it is used at a low dose (non-patent document 11).